Cyclohexenyl acetic acid compounds

ABSTRACT

WHEREIN: R1, R2 AND R3 ARE HYDROGEN OR LOWER ALKYL; N IS 1 TO 4; AND X IS HYDROXYL, AMINO, ALKYLAMINO OR HYDROXYLAMINO. THESE COMPOUNDS POSSESS ANALGESIC AND ANTIINFLAMMAROTY PROPERTIES.   (CH2)N-CH2-CH2-)   (4-(Z-CO-C(-R1)(-R2)-)CYCLOHEX-1-EN-1-YL)-C(-R3)&lt;(-CH2-   CYCLOHEXENYL ACETIC ACID COMPOUND OF THE FORMULA

United States Patent 3 801 628 CYCLOHEXENYL Acnrlc ACID COMPOUNDS MichelVincent, Bagneux, Georges Remond, Paris, and Jean-Claude Poignant,Wissous, France, assignors to Societe en nom Collectif Science Union etCie, Societe US. Cl. 260-5005 H 4 Claims ABSTRACT OF THE DISCLOSURECyclohexenyl acetic acid compounds of the formula (CHDH R3 LV-Gi- R: 8wherein:

R R and R are hydrogen or lower alkyl; '21 is l to 4; and X is hydroxyl,amino, alkylamino or hydroxylamino.

These compounds possess analgesic and antiinfiammatory properties.

This application is a division of our co-pending application Ser. No.873,659, filed Nov. 3, 1969, now US. Pat. 3,697,588.

The present invention provides new cyclohexenyl acetic acid compounds ofthe General Formula I:

( n. R. R1

L i-rwherein The new derivatives of the General Formula I were preparedby dehydrating a compound of the General Formula II:

C R1 R2 8 in which R R and R have the meanings defined above and Rrepresents a lower alkyl radical containing 1 to carbon atoms inclusive;and by reacting the so-obtained compound of the General Formula III:

(CHz) R3 I in which R R R and R have the meanings defined above, with acompound of the General Formula IV:

l HX

in which X has the meanings defined above.

The derivatives of the General Formula II are dehydrated by a methodknown per se, such for example, as the method described by G. A. R. K011and K. S. Nargund, J. Chem. Soc. 2461 (1932).

3,801,628 Patented Apr. 2, 1974 ice The derivatives of the GeneralFormula II themselves are prepared according to the Reformatsky reactionfrom 4-cycloalkyl cyclohexanone, prepared according to the method of A.R. Pinder, J. Chem. Soc. 1577 (1956), of the General Formula and froma-bromoester of the general formula in which R R R and R have themeanings defined above.

The new derivatives of the General Formula I, in which X is a hydroxylor hydroxylamino radical, can be transformed into addition salts withmineral or organic bases, such for example, as bases of alkaline oralkaline earth metals, primary, secondary and tertiary amines, such asmono-, diand triethylamines, and heterocyclic bases such, for example,as morpholine, piperazine, piperidine, etc. The present invention alsoprovides these salts.

All the derivatives of the present invention contain at least oneasymmetric carbon atom and thus may be resolved in optical isomers bymethods known per se. The optical isomers of the derivatives of theGeneral Formula I are also included in the present invention.

The following examples illustrate the invention:

EXAMPLE 1 (4-cycl0hexyl-l-cyclohexen-l-yl) acetic acid A solution of 6.1g. (0.024 mol.) of ethyl (4-cyclohexyl-l-cyclohexen-l-yl) acetate, B.P.0.05 mm. Hgzl24- 125 C., prepared according to the methods ofReformatsky and G. A. R. Ken and K. S. Nargund, J. Chem. Soc. 2461(1932), in 268 ml. of N-sodium hydroxide solution and 386 ml. ofethanol, is heated at reflux for 4 hours.

After concentration to dryness, the residue is dissolved into distilledwater and the unsaponifiable products are extracted with ether. Theaqueous layer is acidified until pH with 5 N HCl, and the precipitatedacid is taken out with ether. The ethered solution is washed withdistilled water, dried on calcium sulphate, filtrated and concentratedto dryness. The crystalline residue is recrystallized from 250 ml. ofpentane. 3.3 g. of (4-cyclohexyl-1-cyclohexen-l-yl) acetic acid, M.P.(capillary) 101 C., are obtained, yield: 61.2%.

EXAMPLES 2 TO 9 The following derivatives are prepared according to themethod described in Example 1:

(2) a-(4-cyclohexyl-1-cyclohexen-l-yl) propionic acid: M.P. (capillary):5557 C., starting from ethyl a-(4- cyclohexyl-l-cyclohexen-l-yl)propionate, B.P. 0.01 mm. Hg: 114-118" C., yield: 72.3%, itself preparedfrom ethyl u-(1-hydroxy-4-cyclohexyl cyclohexyl) propionate, B.P. 0.03mm. Hg: 124-126 C., yield: 75.8%, itself prepared from 4-cyclohexylcyclohexanone and ethyl u-bromopropionate, yield: 66.8%-

(3) a-(4-cyc1ohexyl-l-cyclohexen-l-yl) butyric acid: M.P. (capillary):83-85 C., starting from ethyl m-(4- cyclohexyl-l-cyclohexen-l-yl)butyrate, B.=P. 0.03 mm. Hg: -124" C., yield: 55.9%, itself preparedfrom ethyl a-(1-hydroxy-4-cyclohexyl cyclohexyl) butyrate, B.P. 0.01 mm.Hg: 148152 C., yield: 71.4%, itself prepared .from 4-cyclohexylcyclohexanone and ethyl a-bromobutyrate, yield: 59.4%.

(4) a-(cyclohexyl-l-cyclohexen-l-yl) isobutyric acid: M.P. (Kofler)141-142 0., starting from ethyl a-(4- cyclohexyl-l-cyclohexen-l-yl)isobutyrate, B.P. 0.05 mm. Hg: l20-122 C., yield: 47%, itself preparedfrom ethyl a-(l-hydroxy-4-cyclohexyl-cyclohexyl) isobutyrate, B.P. 0.05mm. Hg: 128l32 C., yield: 61.9%, itself prepared from 4-*cyclohexylcyclohexanone and ethyl a-bromo isobutyrate, yield: 62.2%. The sodiumoc-(4-CYC10116XYl-1- cyclohexen-l-yl) isobutyrate, M.P. (Kofler): 14ll42C., was prepared from ot-(4-cyclohexyl-l-cyclohexen-l-yl) isobutyricacid previously obtained, yield: 74%.

(5) c [4 (1-methyl-cyclohexyl)-1-cyclohexen-1-yl] propionic acid: M.P.(capillary): 7074 C., starting from ethyl or [4(l-methyl-cyclohexyl)-l-cyclohexenl-yl] propionate, B.P. 0.07 mm. Hg:129-130 0., yield: 35%, itself prepared from ethyla-[1-hydroxy-4-(lmethyl-cyclohexyl) cyclohexyl] propionate, B.P. 0.02mm. Hg: 134136 C., yield: 60.7%, itself prepared from4-(l-methyl-cyclohexyl) cyclohexanone and ethyl orbromopropionate,yield: 66.5%.

6) oz [4 (l methy1-cyclopentyl)-l-cyclohexen-lyl] propionic acid: M.P.(capillary): 68-70 C., starting from ethyl a- [4- l-methyl-cyclopentyl)-1-cyclohexen-1- yl] propionate, B.P. 0.07 mm. Hg: 120-122 0., yield:72.8%, itself prepared from ethyl a-[1-hydroxy-4-(1- methyl-cyclopentyl)cyclohexyl] propionate, B.P. 0.05 mm. Hg: 120124 0., yield: 74%, itselfprepared from 4 (1 methyl-cyclopentyl) cyclohexanone and ethylabromopropionate, yield: 74.6%.

(7) a [4 (1 butyl-cyclopentyl)-l-cyclohexen-l-yl] propionic acid:starting from ethyl a-[4-(1-butyl-cyclopentyl) 1 cyclohexen 1yl]propionate, itself prepared from ethyl a-[1-hydroxy-4-(IbutyI-cyclopentyl) cyclohexyl1propionate, itself prepared from4-(1-butyl-cyclopentyl) cyclohexanone and ethyl a-bromopropionate.

(8) c: [4 (1 ethyl-cycloheptyl)-1-cyclohexen-l-yl] propionic acid:starting from ethyl u-[4-(1-ethyl-cycloheptyl)-1-cyclohexen-1-yl]propionate, itself prepared from ethyla-[1-hydroxy-4-(l-ethyl-cycloheptyl) cyclohexyl] propionate, itselfprepared from 4-(1-ethyl-cycloheptyl) cyclohexanone and ethyla-bromopropionate.

(9) oz (4 cyclooctyl 1 cyclohexen-l-yl) buty-ric acid: starting fromethyl a-(4-cyclooctyl-l-cyclohexen-lyl) butyrate, itself prepared fromethyl u-(l-hydroxy-4- cyclooctyl cyclohexyl) butyrate, itself preparedfrom 4- cyclooctyl cyclohexanone and ethyl a-bromobutyrate.

EXAMPLE 10 (4-cyclohexyl-l-cyclohexen-l-yl) acetohydroxarnic acid Ahydroxylamine solution was prepared starting from 9.25 g. (0.13 mol) ofhydroxylamine hydrochloride and 3.17 g. (0.13 atom-gramme) of sodium in60 ml. of ethanol. The sodium chloride formed was filtrated and 22 g.(0.088 mol) of ethyl (4-cyclohexyl-l-cyclohexen-l-yl) acetate and asolution of sodium ethylate (prepared starting from 2 g. (0.088atom-gramme) of sodium in 51 ml. of ethanol) were added to the filtratewhile stirring and maintaining the temperature within the range of from0 to C. The mixture was then allowed to stand for 48 hours at roomtemperature, and concentrated to dryness.

The residue was dissolved in 1500 ml. of water and the solutionacidified by hydrochloric acid until pH (4-cyclohexyl-l-cyclohexen-l-yl)acetohydroxamic acid was suctioned off, washed with distilled water,dried and crystallized in a water-ethanol solution. M.P. (capillary):165-168 C., with decomposition, yield: 52.4%.

4 EXAMPLES 11 TO 12 EXAMPLE 13 a-(4-cyclohexyl-l-cyclohexen-l-yl)propionamide M.P. (Kofler): -141 C. (cyclohexane), starting from ethylu-(4 cyclohexyl 1 cyclohexen-l-yl) propionate and an ammoniacalsolution, yield: 50%.

EXAMPLE 14 N-ethyl u-(4-cyclohexyl-l-cyclohexen-l-yl) pripionamide M.P.(capillary): 101-102" C. (pentane/cyclohexane), starting from ethyla-(4-cyclohexyl-l-cyclohexen-l-yl) propionate and monoethylamine, yield:31.6%.

The cyclohexenyl acetic acid derivatives and their physiologicallytolerable salts of the present invention are valuable pharmaceuticalproducts having especially analgesic and antiinflammatory properties.

The toxicity studied in mice showed that their LD varies from to 300mg./kg. by the intraperitoneal route and from 750 to 2000 mg./kg. by theoral route.

The antiinflammatory activity was demonstrated according to the methodof C. H. Winter et al. (Proc. Soc. Exp. Biol. Med. 3,544 1962) It wasobserved that the new compounds administered at doses of 40 to 80 mg./kg. P.O., decrease from 19 to 58% the plantar oedema of the rats pawinduced by carrageenine.

The analgesic activity was studied in rats by the method of L. O.Randall and J. J. Sellito (Arch. Internat. Pharmacodyn. 111,409 (1957)It was noted that the new derivatives administered at doses of 40 to 80mg./kg. P.O., increase the threshold of pain-perception from 16 to 137%.

The invention further includes pharmaceutical preparations containing aderivative of the General Formula I or a physiologically tolerable saltthereof in admixture or conjunction with a pharmaceutically suitablecarrier such, for example, as distilled water, glucose, lactose, talc,starch, cocoa butter, etc. The pharmaceutical forms may be: tablets,drages, capsules, suppositories or solutions for oral, rectal orparenteral administration at doses from 50 to 500 mg, 1 to 5 times perday.

We claim:

1. Cyclohexenyl acetic acid compounds of the formula:

wherein:

R R, and R are selected from the group consisting of hydrogen and loweralkyl containing from 1 to 5 carbon atoms inclusive:

n is an integer from 1 to 4 inclusive; and

X is hydroxylamino; and

salt, thereof with pharmaceutically acceptable bases.

2. A compound of claim 1 which is a-(4-cyc1ohexyl-1- cyclohexen-l-yl)propionohydroxamic acid.

3. A compound of claim 1 which is (4-cyclohexyl-1- cyclohexen-l-yl)acetohydroxamic acid.

4. A compound of claim 1 which is a-(4-cyc1ohexyl- 1-cyclohexen-1-yl)butyrohydroxamic acid.

6 References Cited UNITED STATES PATENTS 3,479,396 11/1969 Buu-Hoi eta1. 260-500.5 H 3,481,940 12/1969 Levy 260-500.5 H 3,697,588 10/ 1972Vincent et al. ZOO-500.5 H

FOREIGN PATENTS 1,584,641 10/1968 France 260-5005 H JOSEPH E. EVANS,Primary Examiner US. Cl. X.R.

